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Errors in chromosomal segregation can lead to the loss or gain of chromosomes in daughter cells, a condition known as aneuploidy. In humans, aneuploidy is a key characteristic of cancer, with an estimated 70-90% of all human solid tumours harbouring aneuploidy genomes [Gordon D J, Resio B, Pellman D. (2012) Nat Rev Genet. 13(3):189-203]. Interrupting mitotic progress of tumour cells using anti-microtubule toxins (e.g. taxol, the best-selling cancer drug ever manufactured) is one of the most successful strategies to treat human cancers and has become the front-line anti-cancer therapy [Jordan, M. A., and Wilson, L. (2004) Nat Rev Cancer 4, 253-265].
More recently, advances in molecularly targeted drug discovery have facilitated the identification of a new generation of antimitotic therapies that target proteins with specific functions in mitosis. However, antimitotic agents often have a narrow therapeutic index, leading to toxic side effects as normal cells as well as cancer cells are targeted by the antimitotic agent. In addition to this undesirable toxicity, cancer cells can rapidly develop drug resistance to this class of drugs, which further limits their clinical efficacy. Thus, there is an urgent need to develop a new generation of antimitotic agents that preferentially eliminate cancer cells over normal cells, while overcoming the resistance to current anti-microtubule toxins in the clinic.
Autophagy (or autophagocytosis) is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes. Autophagy promotes the survival of cancer cells during proteotoxic and metabolic stress by maintaining cellular energy levels [Macintosh, R. L., and Ryan, K. M. (2013) Seminars in Cancer Biology 23, 344-351]. The best known autophagy inhibitor, chloroquine (CQ), has long been used in the treatment and prevention of malaria. Therefore, given its mechanism of action and long use in the treatment of humans, CQ and its derivatives are being investigated in a number of clinical trials to establish if they can also be effective in the treatment of solid tumours. It has also been shown that acquisition of aneuploidy by errors in chromosome segregation, or by treatment with antimitotic agents, causes proteotoxic stress and metabolic alteration in cancer cells that increase autophagosome formation and lysosome-mediated cell degradation of unnecessary or dysfunctional cellular components and proteins [Tang et al., (2011) Cell 144(4):499-512; Siegel J J, Amon A. (2012) Annu Rev Cell Dev Biol. 28:189-214]. Additionally or alternatively, there are very few, if any, therapeutic agents that can be provided to a subject that can act as a chemoprotective agent, that is, an agent that can protect normal cells while allowing cancer cells to be killed.